Treatment Systems Processes and Devices Addressing Cerebral Vasospasm/Vasoconstriction

ABSTRACT

Endovascular treatment of, for example, delayed cerebral vasospasm involves the placing of a microcatheter in the affected vessels followed by the teachings of the instant disclosure, which is clinically improved with comparison to stow infusion of a vasodilating compound. Systems, processes and self-expanding designed stents and stent-like members are featured whereas as stents and stent-like members are retrieved, nothing is left in the vessel.

BACKGROUND OF THE DISCLOSURES

The present disclosures related to therapy and systems for treating theneurovascular system, in particular the present inventions relate toendovascular devices for neurovascular invention designed to impact,extenuate, mitigate or prevent vasospasm/vasoconstriction.

The present inventions relate to systems for treating issues in thebrain and related vasculature from injury, insult or trauma—oftenrelated or secondary to stroke, including acute conditions related tointracranial bleeding and related insults and injury, both from ruptureof aneurysms and attempts to treat them.

This includes both (PCHV) Post-hemorrhagic cerebral aneurysm, DCV (seebelow) and those related conditions from ischemic and hemorrhagic strokewherein vasoconstriction is a modifiable risk factor.

Intracranial aneurysms which rupture, and/or those which are treatedwith traditional endovascular coiling or neurosurgical clippingmethodologies often result in the most feared sequelae of subarachnoidhemorrhage, namely Delayed Cerebral Vasospasm (DCV).

Since DCV constitutes the leading cause of morbidity in patientsadmitted to tertiary care hospitals, it would be expected that advancesin the devices and approaches which have occurred, for example, inendovascular coiling and related techniques would have been used toaddress this ongoing clinical need. Unfortunately, prior to the adventof the instant teachings this has not been the case to the extent thatpractitioners need it to be to achieve optimal clinical outcomes.

OBJECTIVES OF THE DISCLOSURES AND SUMMARIES

Briefly stated, in patients refractory to standard medical treatment,endovascular treatment of, for example, delayed cerebral vasospasminvolves the placing of a microcatheter in the affected vessels followedby the teachings of the instant disclosure, which is believed to beclinically improved with prior existing approaches such as balloondilatation (or dilatation with a COMANECI® brand of device by RapidMedical of Israel or similar) and in comparison to slow infusion of avasodilating compound. Systems, processes and self-expanding designedstents and stent-like members are featured and highlighted. The stentsand stent-like members being recovered and retrieved, nothing is left inthe vessel.

It is respectfully proposed that the traumatic nature of balloondilatation, owing to the paucity of ability to control radial force,militates strongly for a solution to vasospasm, which is moreatraumatic. Likewise, it is optimal to avoid arterial rupture secondaryto over dilation of the vessel, dissection and related sequelae.

Similarly, it is respectfully submitted that local infusion of calciumchannel blockers, such as Nimodipine causes blood pressures to drop (notgood risk for vasospasm patients), is not effective in all patients andis temporary.

Heparin and/or related compounds in treatment-based aliquots, imaging,comprising angiograms, at least a microcatheter and microguidewire, atleast a retrievable self-expanding stent, with radial forced tuned tothe application, and sheath-means or covering and advancing the at leasta retrievable stent to a target zone, for a predetermined time interval.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows an angiogram with ostensive vasospasm issues; and.

FIG. 2 shows a completion angiogram according to the instant teachings;

FIG. 3 similarly shows a severely impacted vessel including vasospasm;

FIG. 4 shows the follow-up shot wherein the vessel is stabilized byaspects of teachings of the present invention, namely deployment of theobjects of the present invention;

FIG. 5 shows that a vessel in spasm, even with nimodipine, can clearlyseen to be blocked;

FIG. 6 also between the arrows shows ho the system of the presentinvention leads the vessels from a first vasospasmed state to a secondpatent state;

FIG. 7 shows an exemplary stenting-means, have a multiplicity of smallercells which works in conjunction with an elongated system; and

FIG. 8 likewise shows an exemplary stenting-means, have a multiplicityof smaller cells which worn in conjunction with an elongated system toadduce desired levels of radial force.

EXEMPLARY ISSUE BEING ADDRESSED BY THE DISCLOSURES Delayed CerebralVasospasm Secondary to Acute Sub-arachnoid Haemorrhage Background

Sub-Arachnoid Haemorrhage, Delayed Cerebral Vasospasm and DelayedCerebral Injury

Sub-arachnoid haemorrhage (SAH) is a life threatening condition with anincidence of approximately 7-10 per 100000 patient years. The diagnosisrelies upon a high clinical index of suspicion and performing thenecessary investigations that include initially a Computed Tomography(CT) scan of the head alongside CT angiography of the intracranialvessels followed by a delayed lumbar puncture if the CT scan is negativebut suspicion is high.

Of all the causes of subarachnoid haemorrhage ruptured aneurysm arisingfrom the circle of Willis accounts for approximately 85%. Of theremaining 15% that are not attributable to saccular aneurysms, ⅔ arecaused by non-aneurysmal SAH and the remaining 5% are cased by a varietyof rare conditions.

The early prognosis of patients with aneurysmal SAH is most closelycorrelated to three variables:

-   -   1. The neurological condition of the patient on admission.    -   2. The age of the patient    -   3. The amount of blood on the initial CT scan.

Of these variables, the initial neurological condition of the patient atadmission, especially the level of consciousness, is the most importantdeterminant and the causes of an early acute deterioration in the statusof the patient can be due to a variety of different factors such ashydrocephalus, early re-bleeding, or intra-cerebral haematoma.

The goal of treatment for aneurysmal subarachnoid haemorrhage is toprevent re-bleeding of the aneurysm, which has been estimated at between35-40% in the first 4 weeks. This can be done via two well-establishedmethods—endovascular coiling of the aneurysm or neurosurgical clippingof the aneurysm. After the results of the International SubarachnoidAneurysm Trial (ISAT) [8] endovascular coiling has gained widespreadacceptance and the choice between coiling or clipping is often decidedfollowing a multi-disciplinary team meeting between the neurosurgeonsand interventional neuroradiologists. The procedure is performed as soonas possible after the admission of the patient. These treatments areeffective in securing the aneurysm and preventing early re-rupture ofthe aneurysm however, delayed consequences of the initial subarachnoidhaemorrhage can have a devastating effect on the clinical outcome ofpatients. The most feared delayed sequelae of subarachnoid haemorrhageare Delayed Cerebral Vasospasm (DCV) and Delayed Cerebral Injury (DCI).Other terms such as Delayed Ischaemic Neurological Deficit (DIND, DID)are also used in the literature as synonyms.

Delayed cerebral vasospasm is the leading cause of morbidity andmortality in patients who have ruptured intracranial aneurysm and whoare admitted to tertiary care hospitals. Delayed cerebral vasospasmtypically occurs between 3-21 days after the initial insult and may lastfor 12-16 days. At day 7 post-ictus up to 70% of patients willdemonstrate angiographic evidence of cerebral arterial vasospasm andapproximately 30% of patients will go on to develop neurologicaldeficits, termed ‘symptomatic vasospasm’ Angiography done during thistime will often reveal diffuse vasoconstriction of the majorintracranial vessels that frequently involves the terminal internalcarotid artery with some evidence that points towards the location ofthe blood being closely related to the site of vascular vasospasm andthe development of delayed cerebral vasospasm and ischaemia within thisterritory

To date the only drug of proven benefit that is routinely used in theprevention of delayed cerebral vasospasm secondary to subarachnoidhaemorrhage is Nimodipine, a dihydropyridine L-Type voltage gatedcalcium channel antagonist. This is given orally 60 mg every 4 hours for21 days. Allen et al. were the first to publish their findings in theNew England Journal of Medicine with further studies also demonstratingthe protective effects of this medication. However, the exact mechanismas to how calcium channel antagonists prevent or relieve vasospasm isnot clearly understood and the evidence about efficacy and dosage isbased on a single large trial. It is important to note that without thedata from this single large trial the advantage of nimodipine in thesepatients cannot be statistically seen. Therefore, the use of nimodipineis not without question.

In patients that develop cerebral vasospasm there is a risk ofinfarction that can be widespread. Therefore, in order to preventinfarctions from developing medical treatment is optimised to attempt tomaintain perfusion. This involves increasing the blood pressure,normally between 160-200 mmHg (if the patient has had the aneurysmtreated), haemodilution and hypervolaemia. Despite this some patientscontinue to deteriorate and in these patients endovascular treatmentoptions are used.

In patients refractory to standard medical treatment endovasculartreatment of delayed cerebral vasospasm involves the placing of amicrocatheter in the affected vessels followed by the slow infusion of avasodilating compound, normally over the course of 5-30 minutes.Numerous different agents have been used including papaverine, as wellas calcium channel antagonists verapamil, nimodipine and nicardipine.All these agents have demonstrated an affect on the cerebral vasospasmand it is believed that agents with longer half-lives may offer a moresustained and long-lasting effect. It is important to note that there isno level 1 evidence to support the use of any of the aforementionedagents, although numerous smaller trials have demonstrated improvementwith different agents used in different institutions.

Alternatively, the spastic vessels can be dilated mechanically usingballoons. There are numerous publications on this technique going backas far as 1984. Improvements in vessel diameters as well as neurologicaldeficits were observed in most studies following balloon angioplasty andsuccessful treatment translated into a reduced incidence of delayedcerebral ischaemia on radiographic imaging in several studies. However,balloon angioplasty is not without risk and vessel rupture and deathhave been reported.

The exact cause for delayed cerebral vasospasm and delayed cerebralinjury is not completely understood, however as outlined above theprevention or early treatment of cerebral vasospasm seems to improvepatient outcome. The present inventors have addressed this issue andoffer for consideration systems of devices effective for the same.

DETAILED DESCRIPTION OF DISCLOSED EMBODIMENTS

The present inventors have discovered effective ways to impactvasospasm, and improved devices to do so and create better clinicaloutcomes.

As briefly summarized above, despite rapid advancement in the minimallyinvasive and neurovascular fields, there does not seem to be asynergistic leveraging of techniques and devices to make outcomes bestfor patients—given the number of tools.

Lessons learned from open and closed cell stenting in the brain, forexample U.S. Pat. Nos. 8,088,140; 8,197,493 each expressly incorporatedby reference above, need to be used to overcome those issues, whichballoon dilatation and pharmacology cannot address adequately in termsof vasospasm.

Turning to FIG. 1, an angiogram shows that within the target brain areavessels are subject to vasospasm, as known to those skilled in the art.

FIG. 2 shows the follow-up shot wherein the vessel is stabilized byaspects of teaching of the present invention;

FIG. 3 similarly shows a severely impacted vessel including vasospasm;

FIG. 4 shows the follow-up shot wherein the vessel is stabilized byaspects of teachings of the present invention, namely deployment of theobjects of the present invention;

FIG. 5 shows that a vessel in vasospasm, even with nimodipine, which canclearly be seen to be blocked;

FIG. 6 also shows by way of the arrow how the system of the presentinvention leads the vessels from a first vasospasmed state to a secondpatent state.

FIG. 7 and FIG. 8 demonstrate what has been discovered, unexpectedlymitigating or preventing vasospasm, namely longer stents with manysmaller cells and radial force which can be tuned for this application.Referring now to FIG. 7, as discussed the nature of thestent/device/stenting-means has a specifically designed cell structurewhich includes many cells generally of an open variety, whereby anextended length (e.g. At least about 50 cm) allows for trackability andflexibility, balanced with a proper amount of control for deployment.

Referring now also to FIG. 8, self-expanding nitinol stenting-means isshown with small cells which deliver optimum control and radial forcefor the treatment of disease. Artisans understand that having accesswith longer stents having smaller cells and radial force tuned to theneurovascular need undergirds much of the instant solution. Since thisproblem was discovered and overcome by the instant teachings, others maynow continue to advance the science of prevention of vasospasms.

Exemplary Indication

The instant teachings uniquely add tools to the practitioner's arsenalfor treating—for example, a cerebral arterial vasospasm secondary tosubarachnoid hemorrhage, trauma or other conditions. Artisans understandthat this method applies to related methods of treatment.

The Procedure for those skilled in the art includes, for example thefollowing steps. Artisans understand swapping steps and substitutionsand additions are all within the scope of the list below, whichcomprises merely guidance as to one approach for performing according tothe present invention:

A guiding catheter should be placed in the Internal Carotid Artery orVertebral Artery.

Heparinization to double ACT-level.

A diagnostic angiogram is performed in order to visualize the locationand extent of the arterial spasm and exclude other pathologies that maybe contraindications to the treatment.

The MCA, ACerA or PCerA is catherized to the M2, A2 or P2 segment with amicrocatheter (MC) and microguidewire. In case this is not necessary orcannot be safely done the tip of the MC may be placed in the M1, A1 orP1.

The microguidewire is removed.

The temporary stent is inserted in the MC and advanced to the tip of theMC.

The temporary stent is kept in place while the MC is withdrawn to thelevel of the proximal end of the stent. The stent is thus deployedwithout being advanced or retracted.

Control angiography through the guiding catheter.

The temporary stent is kept in place for 3-10 minutes.

Resheathing of the temporary stent by advancing the MC while the stentis kept immobile.

Retraction of the MC to the ICA or Vert Art with the stent still inside.

Control angiography through the guiding catheter.

The procedure may be repeated in the same or other vessels.

Nimodipine (Ca+-channel blockers) can be given in the MC during thestent deployment.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the invention are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these described embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the invention so claimed areinherently or expressly described and enabled herein.

As one skilled in the art would recognize as necessary or best-suitedfor performance of the methods of the invention, a computer system ormachines of the invention include one or more processors (e.g., acentral processing unit (CPU) a graphics processing unit (GPU) or both),a main memory and a static memory, which communicate with each other viaa bus.

A processor may be provided by one or more processors including, forexample, one or more of a single core or multi-core processor (e.g., AMDPhenom II X2, Intel Core Duo, AMD Phenom II X4, Intel Core i5, IntelCore I & Extreme Edition 980X, or Intel Xeon E7-2820).

An I/O mechanism may include a video display unit (e.g., a liquidcrystal display (LCD) or a cathode ray tube (CRT)), an alphanumericinput device (e.g., a keyboard), a cursor control device (e.g., amouse), a disk drive unit, a signal generation device (e.g., a speaker),an accelerometer, a microphone, a cellular radio frequency antenna, andnetwork interface device (e.g., a network interface card (NIC), Wi-Ficard, cellular modem, data jack, Ethernet port, modem jack, HDMI port,mini-HDMI port, USB port), touchscreen (e.g., CRT, LCD, LED, AMOLED,Super AMOLED), pointing device, trackpad, light (e.g., LED), light/imageprojection device, or a combination thereof.

Memory according to the invention refers to a non-transitory memorywhich is provided by one or more tangible devices which preferablyinclude one or more machine-readable medium on which is stored one ormore sets of instructions (e.g., software) embodying any one or more ofthe methodologies or functions described herein. The software may alsoreside, completely or at least partially, within the main memory,processor, or both during execution thereof by a computer within system,the main memory and the processor also constituting machine-readablemedia. The software may further be transmitted or received over anetwork via the network interface device.

While the machine-readable medium can in an exemplary embodiment be asingle medium, the term “machine-readable medium” should be taken toinclude a single medium or multiple media (e.g., a centralized ordistributed database, and/or associated caches and servers) that storethe one or more sets of instructions. The term “machine-readable medium”shall also be taken to include any medium that is capable of storing,encoding or carrying a set of instructions for execution by the machineand that cause the machine to perform any one or more of themethodologies of the present invention. Memory may be, for example, oneor more of a hard disk drive, solid state drive (SSD), an optical disc,flash memory, zip disk, tape drive, “cloud” storage location, or acombination thereof. In certain embodiments, a device of the inventionincludes a tangible, non-transitory computer readable medium for memory.Exemplary devices for use as memory include semiconductor memorydevices, (e.g., EPROM, EEPROM, solid state drive (SSD), and flash memorydevices e.g., SD, micro SD, SDXC, SDIO, SDHC cards); magnetic disks,(e.g., internal hard disks or removable disks); and optical disks (e.g.,CD and DVD disks).

Furthermore, numerous references have been made to patents and printedpublications throughout this specification. Each of the above-citedreferences and printed publications are individually incorporated hereinby reference in their entirety.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

1. A treatment system for cerebral arterial vasospasm which comprises incombination: a guide catheter effective for emplacement in the ICA/VCA;Heparin and/or related compounds in treatment-based aliquots; Imaging,further comprising, angiograms; At least a microcatheter andmicroguidewire; At least a retrievable stent, with radial forced tunedto the application; namely, less force than a dilatation balloon and,Sheath-means for covering and advancing the at least a retrievable stentto a target zone, for a predetermined time interval.
 2. The system ofclaim 1, wherein said at least a retrievable stent is self-expandingnitinol.
 3. The system of claim 2, wherein said at least a retrievablestent is self-expanding and at least one of open and closed celled,whereby the radial force is less traumatic than vasospasm inducingalternatives, such as dilatation balloons which damage theextra-cellular matrix (ECM).
 4. The system of claim 3, wherein said atleast a retrievable stent is self-expanding and at least of open andclosed celled, whereby the radial force is less traumatic than vasospasminducing alternatives, and the stents/stent-like members beingretrieved, nothing is left in the vessel.
 5. The system of claim 4,whereby said at least a retrievable stent-means is self-expanding, andfurther comprising Ca+-channel blockers for use in the MC during stentdeployment, as needed.
 6. The system of claim 5, wherein at least aretrievable stent-means is removable, said devices having at least adrug covering or coating selected from the group of Everolimus;Paclitaxel; Sirolimus; Corolimus and any related compounds, salts,moieties which potentially reduce risk of thrombosis, lumen loss andrelated challenges.
 7. A Kit, comprising, in combination: At least aguide catheter system; At least a self-expanding sheath and retrievablestenting-means; Further comprising an elongated structure ranging fromapproximately 20 cm to at least about 50 cm in length, the radial forcedesigned to stretch but not damage the ECM; A plurality of cells beingsmaller cells disposed about the stenting-means, whereby radial force ismaintained within a range that does not cause the vessel to recoil orvasoconstrict, and; Digital and hard copy instructions for use, imagingand electronic links to databases for patients, care-givers and relatedprocedures.
 8. The Kit of claim 14, further comprising: Instructions tomaintain the retrievable stenting means in situ for at least about 5, 7,10 or more minutes.
 9. The Kit of claim 14, further comprising:Instructions to maintain the retrievable stenting means in situ forenough time to stretch but not damage the ECM.
 10. An improved vesselpatency system, which comprises, in combination: a stent-means/devicefor deployment in intracranial arteries experiencing vasospasm, in orderto expand vessels to their optimal diameter and remain patent after thedevice is re-sheathed.
 11. The improved vessel patency system of claim10, further comprising: the stent-means/device being self-expandingnitinol with small cells.
 12. The improved vessel patency system ofclaim 11, further comprising: said stent-means/device beingself-expanding nitinol which adduces optimum control and radial force tomitigate/extenuate or prevent vasoconstriction/vasospasm, withoutdamaging the ECM.
 13. The improved vessel patency system of claim 19,further comprising: a device ranging from approximately 2-6 mm indiameter and from at least about 20 cm to approximately 50 cm in length.14. The system of claim 13, used for patients' refractory to standardmedical treatment.
 15. The system of claim 13, whereby an adjustableclot retriever is included with or substituted or the stent-meansdevice.
 16. The system of claim 15, whereby an adjustable clot retrieveris optionally included.
 17. The system of claim 16, whereby smoothvascular muscles are stretched, but no harm to the ECM occurs.
 18. Thesystem of claim 15, whereby smooth vascular muscles are stretched, butno harm to the ECM occurs.